Chronic fatigue has genetic roots

The largest study yet of chronic-fatigue syndrome (CFS) has revealed a battery of genetic changes that might explain how the mystery disease arises.

The condition, sometimes called myalgic encephalomyelitis (ME), causes exhaustion and problems with sleep and memory. It was dubbed 'yuppie flu' when it came to public attention in the 1990s, because of the view that sufferers were simply burned out or that the symptoms were psychosomatic.

But although some doctors remain sceptical, many now take the syndrome seriously; it is estimated to affect one million people in the United States alone. But researchers have struggled to find an underlying cause for a disease that weakens the entire body yet has no obvious physical basis.

Researchers at the US Centers for Disease Control and Prevention (CDC) in Atlanta tackled the problem in a new way. They handed four teams of scientists a massive set of information about the symptoms and biology of CFS patients, and challenged them to pull out anything that might explain the disease.

One study showed that patients with CFS tend to have a characteristic set of changes in 12 genes that help the body respond to stress. They showed that a particular combination of gene sequences could predict whether a patient had CFS with over 75% accuracy.

The teams have now published their results in 14 papers in the journal Pharmacogenomics1, producing what they say is the most comprehensive picture of the disease's roots so far. "CFS is a real bodily dysfunction," says Ben Goertzel of Biomind, a biotechnology company based in Rockville, Maryland, who led one of the groups. "The idea that these people are just tired is pretty clearly refuted by this batch of results."

On call

CDC investigators zeroed in on Wichita, Kansas, telephoning residents to assess whether they had symptoms of CFS. They did this, rather than recruit patients from a clinic, because most people with the condition are never diagnosed.

The team identified 227 patients and a comparable healthy group, and brought them in for two days of study. The researchers collected information about subjects' sleep, memory, and nervous systems. They also took blood samples and analysed the sequence of a handful of genes implicated in CFS, and the activity of 20,000 more using gene chips.

Next, four research teams were tasked with using computer algorithms to sift these data for features of the patients' biology, such as genetic sequences, that matched their symptoms. The CDC called it the CFS Computational Challenge.

A similar challenge might help to crack other unfathomable diseases, such as autism, says CDC Director Julie Gerberding: "This approach is likely to work for a number of vexing public-health issues."

Domino effect

The new results fit the existing idea that people develop CFS when events such as infections, injury and trauma disrupt the hypothalamic-pituitary adrenal axis, which is activated by physical and emotional stress. Eventually this has effects throughout the body on the immune and other systems, causing symptoms.

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The researchers suspect that people with CFS fall into four or five different categories with slightly different conditions. They hope to find a profile of genes and proteins to diagnose CFS and its subtype. This could help to select the best treatment.

For now, it's important for different laboratories to repeat these studies, says Leonard Jason, an expert in CFS at DePaul University, Chicago. "It's really the beginning. We're talking decades of work."